One the most common techniques for measuring blood glucose requires removal and subsequent analysis of a sample of the patients blood using reagent-strip reflectance photometry. This technique is still considered to be the most accurate method for obtaining an absolute reading of blood glucose. However, this technique is painful and also undesirable in cases where it is necessary to monitor blood glucose continuously over long periods of time and preferably noninvasively. Moreover, the reagent-strip method is known to be technique sensitive (both in terms of the method used to read the reagent strip and source of blood used for the analysis, i.e., capillary, venous or arterial blood). Furthermore, instrument calibration at the factory may drift in the field due to the decay in enzyme activity or humidity-mediated hydration of the strips. Most importantly, an intermittent invasive technique is not suitable for continuous monitoring of blood glucose or for controlling an artificial pancreas device which can automatically and continuously inject insulin in response to a specific demand to a diabetic patient
Many methods and devices have been developed up to now for the determination of glucose in vitro or in vivo by optical means. Progress towards the development of continuous blood glucose monitoring methods is disclosed in "Blood Glucose Sensors: An Overview", by Peura R. A. and Mendelson Y., (Proceedings of the IEEE/NSF Symposium on Biosensors, 1984).
In PCT application WO No. 81/00622, there is disclosed an IR absorption method and apparatus for determining glucose in body fluids. According to this reference, absorption spectra of serum or urine, both transmissive or reflective, i.e., due to back-scattering effects, are measured at two distinct wavelengths .lambda..sub.1 and .lambda..sub.2- .lambda..sub.1 being typical of the substance of interest and .lambda..sub.2 being roughly independent of the concentration of the substance of interest. Then the pertinent measured data are derived from calculating the ratio of the absorption values at .lambda..sub.1 and .lambda..sub.2, the bands of interest being in the range of 940-950 cm.sup.-1 (10.64-10.54 .mu.m) and 1090-1095 cm.sup.-1 (9.17-9.13 .mu.m), respectively. In this reference, the source of irradiation is provided by a CO.sub.2 laser.
Swiss Patent No. CH-612.271 discloses a non-invasive method to determine biological substances in samples or through the skin using an attenuated total reflection (ATR) prism directly placed against a sample to be analyzed (for instance the lips or the tongue). The refractive index of the wave-guide being larger than that of the sample (optically thinner medium), the beam propagates therein following a totally reflected path. The only interaction thereof with the thinner medium (to be analyzed) being that of the "evanescent wave" component at the reflection interface (See also Hormone & Metabolic Res/suppl. Ser. (1979), p. 30-35). When using predetermined infrared wavelengths typical of glucose absorption, the beam in the ATR prism is attenuated according to the glucose concentration in the optically thinner medium. This attenuation is ascertained and processed into glucose determination data.
U.S. Pat. No. 3,958,560 discloses a non-invasive device for determining glucose in a patient's eye. The device comprises a contact-lens shaped sensor device including an infrared source applied on one side of the cornea and a detector on the other side thereof. Thus, when infrared radiation is applied to the area being measured, light is transmitted through the cornea and the aqueous humor of the eye to the detector. The detected signal is transmitted to a remote receiver and a read-out device providing data on the concentration of glucose in the patient's eye as a function of the specific modifications undergone by the IR radiations when passing through the eye.
GB Patent Application No. 2,033,575 discloses a detector device for investigating substances in a patient's blood stream, namely CO.sub.2, oxygen or glucose. The key features of such a detector comprises use of radiation directed into the patient's body, and receiving the attenuated optical radiations backscattered or reflected within the patients body i.e., from a region below the skin surface. The detected signal is thereafter processed into useful analytical data. Optical radiations include UV as well as IR radiations.
Other references refer to the measurement or monitoring of other bioactive parameters and components such as blood flow, oxyhemoglobin and deoxy hemoglobin. Because of their close analogies with the aforementioned techniques, they are also worth reviewing here.
U.S. Pat. No. 3.638,640 discloses a method and an apparatus for measuring oxygen and other substances in blood and living tissues. The apparatus comprises radiation sources and detectors disposed on a patient's body, for instance about the ear to measure the intensity passing therethrough or on the forehead to measure the radiation reflected therefrom after passing through the blood and skin tissue. The radiations used belong to the red and very near infrared region, for instance wavelengths of 660, 715 and 805 nm. The number of different wavelengths used simultaneously in the method is equal to the total of at least one measuring wavelength typical for each substance present in the area under investigation (including the substance(s) to be determined) plus one. By an appropriate electronic computation of the signals obtained after detection from absorption at these diverse wavelengths useful quantitative data on the concentration of the substance to be measured are obtained irrespective of possible changes in certain of the measurement conditions such as displacement of the test appliance, changes in illumination intensity and geometry, changes in the amount of blood perfusing the tissue under investigation and the like.
GB Patent Application No. 2,075,668 describes a spectrophotometric apparatus for measuring and monitoring in-vivo and non-invasively the metabolism of body organs, e.g., changes in the oxido-reduction state hemoglobin and cellular cytochrome as well as blood flow rates in various organs such as the brain, heart, kidney and the like. The above objects are accomplished by optical techniques involving wavelengths in the 700-1300 nm range which have been shown to effectively penetrate the body tissues down to distances of several mm. Thus in FIG. 14 of that reference there is disclosed a device involving reflectance type measurements and comprising a light source for injecting light energy into a waveguide (optical fiber bundle) applied to the body and disposed in such a way (slantwise relative to the skin) that the directionally emitted energy which penetrates into the body through the skin is reflected or backscattered by the underlying tissue to be analyzed at some distance from the source. The partially absorbed energy then reaches a first detector placed also over the skin and somewhat distantly from the source Another detector placed coaxially with the source picks up a back radiated reference signal. Both the analytical and reference signals from the detectors are fed to a computing circuit, the output of which provides useful readout data concerning the sought after analytical information.
Although the aforementioned techniques have merit some difficulties inherent thereto still exist. These difficulties are mainly related to the optical properties of the radiations used for making the measurements. Thus, radiation penetration into the skin depends on the action of absorbing chromophores and is wavelength-dependent, i.e., the light in the infrared range above 2.5 .mu.m is strongly absorbed by water and has very little penetration capability into living tissues containing glucose and, despite the highly specific absorption of the latter in this band, it is not readily usable to analyze body tissue volumes at depths exceeding a few microns or tens of microns. If exceptionally powerful sources (i.e., CO.sub.2 laser) are used, deeper penetration is obtained but at the risk of burning the tissues under examination. Conversely, using wavelengths below about 1 .mu.m (1000 nm) has the drawback that, although penetration in this region is fairly good, strong absorbing chromophores still exist such as hemoglobin, bilirubin and melanin. By comparison specific absorptions due to glucose are extremely weak which provides insufficient sensitivity and accuracy for practical use in the medical field. In addition, the ATR method which tries to circumvent the adverse consequences of the heat effect by using the total internal reflection technique only enables investigation to depths of tissues not exceeding about 10 .mu.m which is insufficient to obtain reliable glucose determination information.
U.S. Pat. No. 4,655,225 describes a method for the spectrophotometric determination of glucose in the blood stream or tissue by measuring the optical near infrared absorption of glucose at 1575, 1765, 2100 and 2270+or -15 nm where typical glucose absorption bands exists. The measured values are compared with reference values obtained in the range of 1100 to 1300 nm or in narrow regions situated on both sides of the measuring bands but outside the area where glucose absorbs strongly and where the errors due to background absorptions by the constituents of the surrounding tissues or blood containing the glucose are of reduced significance or can be quantitatively compensated.
Although the above referenced patent has merit some difficulties inherent in the technique still exist. These difficulties are related to the near infrared optical absorption properties of glucose and water. FIG. 4 of the above reference patent U.S. Pat. No. 4,655,225, shows the change in optical density plotted as a function of glucose concentration between 0 and 1.0 mol/1 for two selective wavelengths of 2100 and 1100 nm. That figure indicates correctly that the optical absorption of glucose measured at near infrared wavelengths of 2098 nm increases proportionally with glucose concentration. It furthermore indicates that the optical absorption of glucose measured at a near infrared wavelength of 1100 nm decreases slightly with glucose concentration. But it is also apparent from this figure that for normal physiological glucose concentrations, which are generally in the range between 80-110 mg/dl (0.004-0.006 mol/1), the change in optical density measured at a near infrared wavelength of 2098 is extremely small. Furthermore, even for a higher glucose concentration typically found in diabetic patients (300-600 mg/dl or 0.0166-0.033 mol/1), the change in the optical density is still small. Therefore, if the technique disclosed in the above patent is utilized as indicated, in practice, an extremely small signal change would be measured by the optical detector and then processed by electronic circuitry. Thus, the signal to noise ratio will be a major limiting factor in the practical implementation of the techniques of U.S. Pat. No. 4,655,225 as a non-invasive glucose analyzer for measuring the concentration of glucose found in humans. Furthermore, in addition to the near infrared absorption of glucose as shown in FIG. 4 of that embodiment, the light intensity either transmitted through or reflected from tissue at this characteristic wavelength will be even smaller than shown because of the presence of other absorbing components in the blood and interstitial fluid such as proteins and other tissue constituents which absorb radiation at this selected wavelength.